It for some time has been recognized that a number of trophic factors, due to their stimulation of cell growth and differentiation, may have an enhancement on wound healing.
Several studies measuring the efficacy of epidermal growth fact (EGF) in wound healing have been undertaken with mixed results. Thornton et al., Burns 8, 156-160 (1982) applied EGF topically to scald burns in rats. Only an insignificant healing advantage over control was seen.
Niall et al., J. Surg. Res. 33, 164-169 (1982) reported an enhancing effect on wound healing in mice upon topical administration of EGF.
Brown et al., J. Exp. Med. 163, 1319-1324 (1986), studied the activity of EGF topically applied to wounds in miniature pigs. They report that it increased the rate of epithelialization of split-thickness wounds in vivo.
A fourth paper, Buckley et al., Proc. Natl. Acad. Sci USA 82, 7340-7344 (1985), studied the effects of EGF upon slow release from subcutaneously-implanted sponges in rats. They conclude that local sustained presence of EGF accelerates the process of wound healing.
Studies by Lawrence et al., Surg. Forum 36, 575-577 (1985), and Sporn et al., Science 219, 1329-1331 (1983) both suggest an acceleration of wound healing in rats upon administration of transforming growth factor (TGF), and in Lawrence et al., a further enhancement upon the combined use of TGF, EGF, and platelet-derived growth factor (PDGF).
Shultz et al., Science 235, 350-352 (1987), reported that topically applied transforming growth factor-alpha (TGF-.alpha.) and vaccinia growth factor (VGF) in antibiotic cream accelerated epidermal regeneration in partial thickness dermal burns (second degree) on the backs of pigs.
Leitzel et al., J. Neuroscience Research 8, 413-417 (1982) studied nerve growth factor and found that it was ineffective when applied topically to full-thickness skin wounds in the Syrian hamster.
Leitzel et al., Clinical Research 31, 582A (1983), investigated the effect of a number of topically applied mitogenic preparations, viz., dexamethasone and insulin, PDGF, fibroblast growth factor (FGF), thrombin, Defined medium F for Fibroblasts, liver cell supernatant, EGF, NGF, and colostrum, to wounds in Syrian hamsters. They conclude that none of these agents has any effect on accelerating the healing of skin wounds.
Recently, interest has been generated in the IGFs, insulin-like growth factor-I (IGF-I), also termed Somatomedin C, and insulin-like growth factor-II (IGF-II). Froesch et al., Diabetologia 28, 485-493 (1985), reports (page 490) that "the major effects of IGFs are on growth of cells of mesodermal origin and on differentiation." They further report that the "constant high levels of IGF in the bound form in serum may, therefore, serve several functions: replacement of dying cells, repair mechanisms, matrix synthesis and perhaps also a constant stabilization of cells keeping them from transforming and dedifferentiating."
Froesch et al., Ann. Rev. Physiol. 47, 443-467 (1985) state (page 448), "IGF-II has one-third the potency of IGF-I in stimulating DNA synthesis in human fibroblasts and one-fifth the potency in rat osteoblasts. It is possible that these IGF-II concentrations are sufficient to sustain tissue repair and regenerative processes."
Bhaumick et al., Endocrine Society Abstract 552, June, 1986, report, in studies using a mouse limb bud organ culture, findings that suggest that IGF-II may have a predominant role in undifferentiated cell proliferation whereas IGF-I stimulates differentiation and then proliferation.
Skover et al., Federation Proceedings 43 (4), 992 (1984), in studies using somatomedin-C (IGF-I), suggest that it is a specific stimulus for collagen synthesis in human fibroblasts and, thus, may be an important regulator of wound repair and may have possible applications in the modulation of healing.
In the context of the foregoing, we have discovered that the healing of wounds can be greatly enhanced by topical administration of IGF-II. This is quite unexpected, especially since we have further discovered that IGF-I topically has at best minimal enhancing effect on wound healing.